Unique form of Vitamin B6 Protects Against Complications Related To Diabetes and Aging

by Laurie Barclay, MD, introduction by William Faloon

Pyridoxamine Protects Against Kidney Damage

“There is experimental evidence that pyridoxamine supplementation can be helpful in preventing and delaying diabetic complications,” Prof. Jain says.

In studies of diabetic or obese rats, pyridoxamine protected against kidney damage, as well as against development of retinopathy and neuropathy in diabetic rats. Compounds found in the urine of these rats confirmed that pyridoxamine was acting as an AGE/ALE inhibitor.9

Rats made diabetic by administration of a drug known as streptozotocin tend to develop kidney disease, similar to nephropathy seen in diabetic patients. Interestingly, pyridoxamine limited AGE formation and development of nephropathy in streptozotocin-diabetic rats without affecting control of blood sugar.13

Lipids appear to be an important source of AGEs in the diabetic rat, based on findings that pyridoxamine lowers lipids. Blood levels of cholesterol and triglycerides increase in proportion to AGEs in skin collagen.13 In Zucker rats, pyridoxamine lowered levels of cholesterol and triglycerides, inhibited AGE formation, and protected against kidney and blood vessel damage.13

Zucker rats given pyridoxamine in their drinking water, but not the untreated controls, had lowering of high blood pressure and less thickening of blood vessel walls associated with atherosclerosis. Even more amazing was that markers of kidney damage decreased in the pyridoxamine-treated rats. Blood creatinine levels decreased, as did leakage of total protein and of a specialized protein known as albumin into the urine, nearly returning to levels seen in nonobese rats.13

Similarly, in streptozotocin-diabetic rats, pyridoxamine significantly blocked the increase in albumin found in the urine, and of blood levels of creatinine and lipids.14

Pyridoxamine was as effective as aminoguanidine in correcting these abnormalities reflecting diabetic complications.14 However, pyridoxamine, but not aminoguanidine, improves insulin secretion, glycemic control, and beta-cell regeneration in diabetic animals.12

“Therapeutic effects of pyridoxamine in complications of diabetes were investigated in animal models and in clinical trials,” Prof. Voziyan says. “The most substantial data are available on pyridoxamine’s effects in diabetic nephropathy. In several different animal models, pyridoxamine inhibited increase in albuminuria and serum creatinine; pyridoxamine also ameliorated characteristic pathologic lesions such as increase in glomerular volume and expansion of mesangial matrix.”

In other words, pyridoxamine corrected not only functional markers of diabetic kidney damage, such as albumin in the urine and creatinine in the blood, but also anatomical markers. The glomerulus acts as a filter to control which beneficial compounds are retained in the blood and which waste products are excreted into the urine passing through each nephron, or urine collection unit within the kidney.

Blood volume within the glomerulus, which is an intricate web of capillaries (small blood vessels) surrounding each nephron, is increased in diabetic nephropathy.15 Pyridoxamine appears to reduce this increase in glomerular volume.

Another pathological change in diabetic nephropathy is that material within the glomerulus known as mesangial matrix progressively expands, ultimately blocking glomerular capillaries and hence reducing filtration of blood through the nephrons. One key factor leading to expansion of the mesangial matrix is abnormal glycation of matrix proteins, which interferes with their degradation and turnover.16

Not surprisingly, therefore, by preventing AGE formation, pyridoxamine is uniquely poised to prevent expansion of the mesangial matrix, an important marker of diabetic nephropathy.7

In streptozotocin-induced diabetic rats, PLP (an active form of pyridoxamine) significantly reduced evidence of nephropathy, namely albumin in the urine, glomerular hypertrophy, mesangial expansion, and accumulation of AGEs. Pyridoxamine itself had similar effects, although PLP was more effective.17

Shedding further light on the mechanisms of action of pyridoxamine in protecting kidney function are studies in a rare genetic disorder that results in overproduction of oxalate, leading to kidney stone formation and end-stage renal disease early in life. In an experimental model of this disorder, pyridoxamine cut urinary oxalate excretion by half, compared with untreated animals, and significantly reduced kidney stone formation.18

Another kidney disease in which pyridoxamine may be therapeutic is chronic allograft nephropathy, which occurs when the immune system attacks a transplanted kidney. In an animal model of this condition, pyridoxamine improved kidney function and reduced structural damage by inhibiting AGE formation.19

Pyridoxamine Protects Against Nerve and Eye Damage

“In diabetic animal models, pyridoxamine demonstrated relevant therapeutic effects in the retinal vasculature and in the peripheral nerves,” Prof. Voziyan says.

In a study from Queen’s University of Belfast in Northern Ireland, diabetic rats given pyridoxamine for 29 weeks had dramatically reduced development of retinal damage, whereas those given other antioxidants, namely vitamin E and lipoic acid, did not. Pyridoxamine protected against a wide variety of pathological changes in the diabetic retina, including blockage of small blood vessels, altered gene and protein expression, and accumulation of immunologically active AGE/ALEs.20

A laboratory study from Case Western Reserve University in Ohio showed that pyridoxamine prevented AGE formation in the lens, further supporting its benefits in protecting against the visual loss accompanying aging and diabetes. The same study showed that pyridoxamine reduced oxidative stress and AGE formation in red blood cells and plasma proteins from diabetic rats.22

“Pyridoxamine supplementation has shown benefit in prevention of diabetic nephropathy and retinopathy in experimental diabetes using high-dose supplementation,” Prof. Thornalley says.

Human Studies With Pyridoxamine

Pyridoxamine has shown promise for treatment of diabetic nephropathy, not only in animal models of diabetes, but also in phase 2 clinical trials with diabetic patients.23

“Pyridoxamine efficacy was also investigated in patients with type 1 and type 2 diabetes and overt nephropathy,” Prof. Voziyan says. “In these clinical trials, pyridoxamine significantly reduced the rise in serum creatinine.”

Phase 2 clinical studies of pyridoxamine in patients with kidney disease from type 1 or 2 diabetes were conducted at several specialty centers and were led by a group from the prestigious Joslin Diabetes Center at Harvard Medical School.23 One trial used a dose of 50 mg pyridoxamine given twice daily, whereas the second trial used doses of 250 mg twice daily.

When results from both trials were combined, pyridoxamine significantly decreased AGE formation, as expected. Even more promising was a reduction in the change from baseline in blood levels of creatinine, suggesting a protective effect on kidney function compared with placebo. However, there were no differences compared with placebo in excretion of albumin into the urine.23

Because of its role in combating AGE formation as well as oxidative stress, pyridoxamine is a novel approach being studied clinically for its possible contribution in treatment of diabetic nephropathy and other forms of chronic kidney disease.24

Pyridoxamine May Complement Other Kidney-Protecting Compounds

One of the advantages of using pyridoxamine to support kidney function is that its multiple mechanisms of action are likely to allow it to safely enhance the effects of other therapies—including pharmaceuticals and nutritional supplements—that may protect the kidney from injury related to diabetes or other chronic conditions. Two renal-protective agents identified by Life Extension are CoQ1021 and silymarin.25

Pyridoxamine may be used in concert with prescription therapies used in the management of conditions associated with diabetes. “Both animal studies and clinical trials have shown that pyridoxamine therapy is effective even when used together with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, which are standard anti-hypertensive treatments in diabetes,” Prof. Voziyan says. “This shows that pyridoxamine therapy provides additional benefits compared to existing standard treatments.”

To minimize the formation of advanced glycation end products in your body, avoid foods cooked higher than 250 degrees, especially high-fat, grilled meats and caramelized sugars. Optimally control blood glucose levels. Supplementation with pyridoxamine, antioxidants and other anti-glycating compounds such as carnosine and benfotiamine would be expected to further assist in protecting against glycation-induced protein damage.



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